Jul 2026· International Journal of Molecular Sciences· Vol 27, pp. 6612· 1 citation· 49 references
Medicine
TL;DR
The findings elucidate Girdin signaling as a mediator of excessive neuronal process formation following NRXN2 knockdown, providing mechanistic insight into how the loss of function of NRXN2 leads to aberrant cell morphogenesis at least at the molecular and cellular levels.
Abstract
During development, neurexin-2 (NRXN2) is a cell adhesion molecule localized to presynaptic terminals as well as axonal shafts and immature neurites, where it participates in the regulation of neuronal cell morphogenesis. Given its critical role in early neuronal development, NRXN2 is considered a susceptibility gene product for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the intracellular signaling mechanisms linking NRXN2 deficiency to abnormal neuronal cell morphology remain unclear. Herein, we investigated the molecular basis of excessive cell morphogenesis induced by the knockdown of NRXN2 using the N1E-115 cell line, a model of neuronal morphogenesis characterized by neurite outgrowth. Silencing NRXN2 using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas13 system resulted in a marked enhancement of process elongation. Mechanistically, we found that Girdin (also called GIV or CCDC88A), a non-receptor guanine nucleotide exchange factor for heterotrimeric G proteins, can mediate the excessive process length phenotype. Transfection of either the regulator of G protein signaling (RGS) domain of RGS3, a GTPase-activating protein for G proteins, or the G protein-binding domain of engulfment and cell motility 1 (ELMO1) rescued the excessive process formation. Similar results were obtained in primary cortical neurons. In addition, these interventions normalized downstream Rac1 activity in cells. Together, our findings elucidate Girdin signaling as a mediator of excessive neuronal process formation following NRXN2 knockdown, providing mechanistic insight into how the loss of function of NRXN2 leads to aberrant cell morphogenesis at least at the molecular and cellular levels. These results suggest that signaling through Girdin may contribute to the morphological abnormalities associated with NRXN2-related neurodevelopmental disorders.
This work investigated the molecular basis of excessive neuronal process formation induced by depletion of NLGN2 using the N1E-115 cell line, an established model of neuronal differentiation, and identified the CCDC88A-G protein-ELMO signaling pathway as a key mediator of excessive neuronal morphogenesis following NLGN2 knockdown.
Hideji Yako, Mikito Takahashi, Shiori Tada et al.· International Journal of Mol...· 0 citations
The nervous system relies on billions of neurons connected through trillions of synapses to support vital functions. Despite the importance of this synaptic network, cellular mechanisms dictating synapse formation during human neurodevelopment remain unclear. Long-distance trafficking by the microtubule motor KIF1A is crucial for synaptogenesis and downstream synapse maintenance. Mutations in KIF1A cause KIF1A-Associated Neurological Disorder (KAND). We employed isogenic gene-edited human iPSC-derived neurons to assess effects of disparate pathogenic mutations in KIF1A on synaptic trafficking and function. Null (p.C92*) and hypoactive (p.P305L) mutations delay neurite outgrowth, mislocalize synaptic cargos, and decrease synapse density. Conversely, a hyperactive (p.R350G) mutation supports neurite outgrowth but causes aberrant motility of synaptic vesicle precursors and deficits in microtubule-dependent presynaptic patterning. Functional analysis of neuronal activity reveals delayed synaptic maturation in loss-of-function mutations (p.P305L, p.C92*) and precocious activity in the hyperactive p.R350G mutation. These data provide insights into how KIF1A mutations with distinct molecular-level impacts lead to significant downstream synaptic deficits in human neurons.
Jayne Aiken, Carris Borland, Nicolas Marotta et al.· Journal of Cell Biology· 0 citations
Findings establish OCNDS as a disorder of compartment-specific translational dysregulation driven by impaired CK2α–G3BP1 control of RNA granule homeostasis, and establish G3bp1 knockdown rescues translational and morphological phenotypes across all OCNDS alleles.
The first comprehensive human mechanistic model of PPP1R9A haploinsufficiency using an isogenic CRISPR/Cas9-engineered iPSC system differentiated into cortical neurons is established, providing a human-specific mechanistic framework linking reduced Neurabin I dosage to neurodevelopmental and psychiatric disease risk.
This study indicates that KIF2C may regulate microtubule dynamics to control deep-layer cortical neuron number and organization and modulate neuronal projections and signaling pathways and provides a foundation for understanding the role of KIF2C in neural development.
Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene and characterized by profound impairments in neuronal maturation and synaptic connectivity. Increasing evidence indicates that astrocyte dysfunction contributes to RTT pathogenesis through non-cell-autonomous mechanisms, although the molecular pathways underlying defective astrocyte-neuron communication are only partially understood. Astrocytes are the primary source of cholesterol in the brain and support neuronal maturation and synaptic function by supplying cholesterol through ApoE-containing lipoproteins. Although alterations in brain cholesterol metabolism have been reported in RTT, the underlying cellular mechanisms and their functional consequences remain poorly investigated. Here, we studied cholesterol homeostasis in Mecp2 knock-out (KO) astrocytes and its impact on neuron-astrocyte communication. Mecp2 KO astrocytes exhibited reduced nuclear localization of the transcriptional regulator Srebp2, together with the downregulation of genes involved in cholesterol biosynthesis and transport. These molecular alterations were associated with intracellular cholesterol and desmosterol accumulation, reduced Abca1 expression and defective ApoE lipidation, despite preserved ApoE expression and cholesterol secretion. Importantly, similar alterations were detected in acutely isolated astrocytes and in the cerebral cortex of Mecp2 deficient mice, demonstrating that impaired cholesterol homeostasis extends beyond in vitro models. Functionally, cholesterol supplementation of astrocyte-conditioned medium rescued the synaptic defects induced in wild-type neurons by Mecp2 KO astrocytes. Moreover, cholesterol treatment restored pre- and post-synaptic density, as well as axon initial segment length in Mecp2 heterozygous (HET) neurons. Together, these findings identify defective astrocyte-to- neuron cholesterol trafficking as a key mechanism contributing to neuronal dysfunction in RTT and suggest that strategies aimed at restoring cholesterol functional availability might represent a promising therapeutic avenue for RTT.
Francesca M. Postogna, Noemi Giancroce, C. Cabasino et al.· bioRxiv· 0 citations
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